Elsevier

Cardiovascular Pathology

Volume 8, Issue 3, May–June 1999, Pages 145-151
Cardiovascular Pathology

Articles
Increased Expression of Tumor Necrosis Factor-α in Diabetic Macrovasculopathy

https://doi.org/10.1016/S1054-8807(98)00033-7Get rights and content

Abstract

Large vessel disease, a common feature of diabetes mellitus, appears to run an aggressive course, but its cellular and molecular aspects remain partially elucidated. Although in common atherosclerosis and especially in other forms of accelerated vasculopathy, immunoinflammatory mechanisms participate in the disease process, it is unclear whether this is present in diabetic vasculopathy. We hypothesized that diabetic macrovasculopathy, compared with classical atherosclerosis, is associated with increased immunoinflammatory features and matrix accumulation. In this study, vessel segments obtained after lower-limb amputation for advanced atherosclerotic disease, from type 2 diabetic patients (n = 20; 68.9 ± 10.9 years) and nondiabetic patients (n = 16; 67.1 ± 14.6 years) were analyzed. Histological characteristics (extent of intimal proliferation, cellularity, and fibrosis) were semiquantitatively graded in the two lesion types. Using immunohistochemistry, the presence of T cells and macrophages, accumulation of fibronectin, and expression of tumor necrosis factor- α was also assessed. Histological features of these advanced atherosclerotic lesions were similar in the two lesions examined. By immunohistochemistry, a similar pattern of T-cell and macrophage infiltration and fibronectin accumulation was observed. Nevertheless, increased expression of tumor necrosis factor-α was observed in diabetic lesions (13/19 patients had positive staining), whereas only 2 of 16 lesions from nondiabetic patients had positive staining (p < 0.003), with an odds ratio of 15.17 (confidence interval 2.12–139.5). These data suggest that increased expression of tumor necrosis factor- α observed in the diabetic lesions may reflect an enhanced inflammatory activity associated with the development of vascular lesions in type 2 diabetic patients.

Section snippets

Patients

This prospective controlled clinical study was conducted at Hospital de Clı́nicas de Porto Alegre (a tertiary care center) between April and October 1996. During this period, all vessel segments obtained from both type 2 diabetic and nondiabetic patients submitted to inferior limb amputation for chronic atherosclerotic disease without clinical and laboratorial evidence of gangrene were studied. Type 2 diabetes mellitus was defined according to World Health Organization criteria (16). Exclusion

Patients

Clinical and laboratory characteristics of type 2 diabetic and nondiabetic patients are described in Table 1. There was an increased number of smoking patients in the nondiabetic group (87%) compared with type 2 diabetic patients (40%) (p < 0.05). Also, diabetic patients had higher plasma glucose levels than the control group (p < 0.05). The known duration of diabetes in this group was 19.5 ± 8.8 years, their treatment being diet only (n = 5), insulin (n = 7) and hypoglycemic agents (n = 8).

Histological Analysis

Discussion

In the present study, we characterized increased expression of an immunoinflammatory mediator, TNF-α, in atherosclerotic lesions from type 2 diabetic compared with atherosclerotic lesions from nondiabetic patients. To our knowledge, this is the first report to investigate the presence of an immunoinflammatory reaction associated with advanced human diabetic macrovascular lesions. This may provide mechanistic insights in the pathogenesis of diabetic macrovasculopathy.

Conclusions

In summary, this semiquantitative study demonstrated that, histologically, atherosclerotic lesions from type 2 diabetic and nondiabetic patients share many features. Moreover, immunoinflammatory atherosclerotic features were also present in type 2 diabetes, as T cells and macrophages, as well as changes in the extracellular matrix component fibronectin, were observed. However, an increased amount of TNF-α was evident in type 2 diabetic lesions compared with nondiabetic lesions. This may

Acknowledgements

We are thankful to Dr. Marlene Rabinovitch and Dr. Jorge Luiz Gross for reviewing this manuscript and providing thoughtful comments. We also acknowledge the technical support form the Division of Pathology from the Hospital de Clı́nicas de Porto Alegre, especially the collaboration of Dr. Maria Izabel Edelweiss. We thank Mike Starr from The Hospital for Sick Children, University of Toronto, Canada, for performing the color photomicrographs. This study was supported by a grant to Dr. Clausell

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